The tropane skeleton is a basic structural unit that can lead to compounds with diverse Central Nervous System (CNS) activity. Due to the rigid nature of the structure, the possibility exists for the preparation of highly selective compounds. This application describes the synthesis of tropane derivatives that selectively bind to monoamine neurotransmitters and thus have the potential for the treatment of major depression, Parkinson's disease and attention-deficit hyperactivity disorder (ADD).
Two important central nervous system neurotransmitters are serotonin (5-HT) and dopamine (DA). Together with norepinephrine and epinephrine, these neurotransmitters comprise the group of agents known as the monoamines. Either 5-HT or DA have been implicated in a variety of disorders, including depression, Parkinsons disease, ADD, obesity and cocaine addiction.
Major depression represents one of the most common mental illness, affecting between 5-10% of the population. The disease is characterized by extreme changes in mood which may also be associated with psychoses. It has generally been found that most antidepressant agents exert significant effects on the regulation of monoamine neurotransmitters, including DA, 5-HT and norepinephrine. The tricyclic antidepressants, such as imipramine, are the most commonly used drugs for the treatment of depression. Their ability to inhibit the neuronal uptake of norepinephrine is believed to be a major factor behind their efficacy.
A number of new types of antidepressants have been developed in recent years. Two such compounds that are marketed in the U.S. are trazodone and fluoxetine. Both of these compounds interact with the regulation of 5-HT. Trazodone potentiates the actions of 5-HT while fluoxetine is a potent and selective inhibitor of 5-HT reuptake. 3-Chloroimipramine which inhibits both 5-HT and norepinephrine reuptake has been extensively used as an antidepressant in Europe and Canada. Other compounds which are of current interest or have been examined as antidepressants include fluvoxamine, citalopram, zimeldine, bupropion and nomifensine. All of these drugs inhibit monoamine uptake mechanisms, but differ in selectivity between the dopamine, 5-HT and norepinephrine transporters.
Other syndromes also respond to antidepressant drugs. These include (1) severe anxiety syndromes characterized by panic reactions, and (2) obsessive-compulsive disorder, both of which seem most likely to respond to 5-HT selective agents. Monoamine uptake blockers have also been useful in treatment of chronic pain, neuralgias, migraine, sleep apnea, fibromyalgia, and irritable bowel syndrome.
Parkinson's disease effects about 1% of the population over the age of 65 and leads to serious neurological disorders. The main clinical features of the disease are centered around disruption of motor function, such as walking, speech, eating and other skilled acts. It has been recognized that the disease is the result of dopamine deficiency in the basal ganglia. Thus, drugs that can increase the levels of dopamine have the potential to be effective medications for the treatment of Parkinson's disease. The most effective drug in this regard has been levodopa which acts as a biogenic precursor to dopamine.
Considerable attention has recently been directed to the condition known as attention-deficit hyperactivity disorder. Children with this condition tend to be very active physically but have great difficulty with situations requiring long periods of attention. Consequently, they tend to underachieve academically and can be very disruptive. Furthermore, these behavioral problems often persist in modified forms into adulthood. The condition appears to be associated to the effect of monoamines in the cerebral cortex, which are involved with control of attention. A number of stimulant drugs such as dextroamphetamine, methylphenidate as well as the tricyclic antidepressants, antipsychotic agents and clonidine have been used as medications to control the disorder. Many of these drugs interact with the monoamine uptake transporters.
Another disorder for which inhibitors of monoamine transport are useful therapeutic agents is obesity. In general, sympathomimetic drugs (i.e., those which increase synaptic levels of monoamines) promote weight loss by suppressing appetite. Drugs like mazindol, which act as sympathomimetic agents by blocking monoamine uptake, have been useful in the treatment of obesity.
Cocaine has the following formula: ##STR1## The basic ring structure of cocaine is a tropane ring system.
It has previously been shown that cocaine and related compounds are potent inhibitors of dopamine reuptake and this may lead to compounds with reinforcing properties. In recent years a number of new extremely potent cocaine analogs have been prepared based on the tropane structure (Abraham et al., Journal of Medicinal Chemistry 1992, 35, 141; Boja et al., European Journal of Pharmacology, 1990, 183,329; Boja et al., European Journal of Pharmacology, 1991, 194, 133; Carroll et al., Journal of Medicinal Chemistry, 1992, 35, 969; Carroll et al., Journal of Medicinal Chemistry, 1992, 35, 1813; Carroll et al., Journal of Medicinal Chemistry, 1992, 35, 2497, Cline et al., Journal of Pharmacology and Experimental Therapeutics, 1992, 260, 1174; Cline et al., Synapse, 1992 12, 37; Kozikowski et al., Medicinal Chemistry Research, 1991, 1, 312; Kozikowski et al., Journal of Medicinal Chemistry, 1992, 35, 4764; Lewin et al., Journal of Medicinal Chemistry, 1992, 35, 135; Madras et al., Molecular Pharmacology, 1989, 36, 518). All of these compounds are based on the tropane skeleton and tend to selectively bind to the dopamine transporter. Certain structural variations can lead to compounds that bind with very high selectivity to the dopamine reuptake site (Carroll et al, Journal of Medicinal Chemistry, 1992, 35, 2497). However, all of these tropane derivatives are very similar to each other because they are all derived from cocaine as starting material.
It has now been discovered that if the tropane ring system is modified, particularly at the aryl moiety as hereinafter described, compounds can be produced which are more selective in binding to 5-HT transporters as compared to DA transporters. Since these modified tropanes (as described below) bind preferentially to the 5-HT transporter, they may preferentially block 5-HT transport, thus, increasing synaptic levels of 5-HT. This may be helpful in treating diseases related to 5-HT function. Similarly, tropane analogs can be synthesized which selectively block DA transporters and selectively increase synaptic levels of DA.
In principle, the tropane skeleton is ideally suited to prepare highly selective compounds because it is a rigid structure and tropane derivatives will have rather limited conformational flexibility. Such derivatives may be altered by appropriate structural changes so that analogs favoring binding to either the 5-HT or DA reuptake site could be prepared. The novel chemistry that has been developed, as referred to in our parent application, has enabled preparation of a much wider range of tropane analogs than was previously accessible, leading to novel structures with selective biological activity.
Accordingly, it is a primary objective of the present invention to provide a process for preparing tropane analogs which are selective inhibitors of either 5-HT or DA reuptake.
Another primary objective of the present invention is to prepare a range of tropane analogs which can be investigated as drugs for the treatment of chronic depression.
A still further objective of the present invention is to provide a wide range of tropane derivatives which can be systematically used and tested to determine structure-activity relationships for binding at dopamine, 5-HT and norepinephrine transporters.
A further objective is to provide a treatment system for diseases whose course can be altered by patient treatment with compounds that selectively bind to either the 5-HT or DA reuptake site and therefore prevent neurotransmissions at this site.